Alcohol consumption is the third largest risk factor for premature mortality in the world [1]. Insights into the mechanism of action that drives consumption will lead to better drinking cessation therapies. Alcohol has been shown to activate dopaminergic (DAergic) neurons within the mesocorticolimbic pathway, the major brain reward circuit activated by all other known drugs of abuse. Specifically, nicotinic acetylcholine receptor (nAChRs) have been implicated in alcohol consumption and reward. Neuronal nAChRs are pentameric ligand gated ion channels, with twelve distinct subunits identified (alpha2-alpha10, beta2-beta4). The subunit composition determines the biophysical and pharmacological properties of the receptor. Subunit composition of nAChRs involved in alcohol consumption and reward are currently unknown. Previously, our lab has shown that nAChRs that contain the alpha4 subunit (alpha 4* nAChRs) are critically involved in alcohol consumption and reward. In addition, preliminary data suggests that nAChRs involved in alcohol consumption and reward may also contain the alpha 6 subunit. Interestingly, there are polymorphisms in the alpha 6 nAChR subunit gene, CHRNA6, associated with heavy alcohol consumption in human drinkers [12]. The alpha 6 subunit is also highly expressed in DAergic neurons in the ventral tegmental area (VTA), which is part of the mesocorticolimbic pathway. Thus, I hypothesize that alpha 6* nAChRs are involved in alcohol consumption and reward, as well as activation of DAergic VTA neurons. To test this hypothesis, I will use pharmacology, genetics, electrophysiology and behavioral assays. In Aim 1, I will use biophysical approaches in mouse midbrain slices to test the hypothesis that alpha 6* nAChRs play a critical role in ethanol-induced activation of VTA DAergic neurons. In Aim 2, I will use drinking- in-the-dark and conditioned place preference to measure alcohol consumption and reward, respectively. These assays will be done in combination with brain region-selective infusions of alpha 6 nAChR antagonists and genetic mouse models that do not express CHRNA6. It is anticipated that the results from these experiments will provide insights into the molecular mechanism underlying acute alcohol consumption and reward.